Enantiospecific analysis by capillary electrophoresis: applications in drug metabolism and pharmacokinetics

Enantiospecific analysis has an important role in drug metabolism and pharmacokinetic investigations and its now no longer acceptable to determine total drug, or metabolite, concentrations following the administration of a racemate. Inspite of the fact that capillary electrophoresis (CE) has become an essential technique in pharmaceutical and enantiospecific analysis, the chromatographic methodologies remain the most commonly used approach for the determination of the enantiomeric composition of drugs in biological fluids. The application of CE to bioanalysis has been slow, which is in part associated with the complexity of biological matrices together with the relatively poor concentration limits of detection achievable. However, as a result of its versatility, high separation efficiency, minimal sample requirements, speed of analysis and low consumable expense CE is likely to play an increasingly significant role in the area. This review present an overview of enantiospecific CE in bioanalysis in which the approaches to enantiomeric resolution and the problems associated with biological matrices are briefly discussed. The application of enantiospecific CE to samples of biological origin is illustrated using examples where the methodology has either solved an analytical problem, or provided a useful alternative to the currently available chromatographic methods. Such improvements in methodology are associated with either the high separation efficiency and/or microanalytical capabilities of the technique. Enantiospecific CE will not replace the chromatographic methodologies but does provide the bioanalyst with a useful addition to his armamentarium.     

Additive global noise delays Turing bifurcations

We apply a stochastic center manifold method to the calculation of noise-induced phase transitions in the stochastic Swift-Hohenberg equation. This analysis is applied to the reduced mode equations that result from Fourier decomposition of the field variable and of the temporal noise. The method shows a pitchfork bifurcation at lower perturbation order, but reveals a novel additive-noise-induced postponement of the Turing bifurcation at higher order. Good agreement is found between the theory and the numerics for both the reduced and the full system. The results are generalizable to a broad class of nonlinear spatial systems.     

Ring fragmentation processes resulting from acid catalysed diazo ketone cyclisations

The initial products from the cyclisation of hexahydrophenanthryl diazo ketones with participation by either the alkene bonds or the aromatic ring (Ar_1,4) undergo rearrangement by 1,2 bond shifts or unexpected bond fission. Benzocyclo-octanyl ketones were formed from the latter process.     

Identification of quinoline nitration products by NOE

The structures of the products from the nitration of 2- and 4-oxodihydroquinolines were assigned based on Nuclear Overhauser Effects of their nmr spectra and confirmed by unambiguous synthesis.     

Fluorescence switching of imidazo[1,5-a]pyridinium ions: pH-sensors with dual emission pathways

Imidazo[1,5-a]pyridinium ions are identified as highly emissive and water-soluble fluorophores accessed by an efficient three-component coupling reaction. Synthetic modifications of groups conjugated to the polyheterocyclic core are shown to profoundly impact the emission properties of these molecules. Notably, two structural isomers of functionalized imidazo[1,5-a]pyridinium ions were found to exhibit distinct de-excitation pathways, which are responsible for either a fluorescence turn-on or ratiometric response to pH change.     

Application of a radial compression column to the high-performance liquid chromatographic separation of the enantiomers of some 2-arylpropionic acids as their diastereoisomeric s-(-)-1-(naphthen-1-yl)ethylamines

The enantiomers of 2-phenylpropionic acid and four congeneric anti-inflammatory drugs were separated as their diastereoisomeric amides with S-(-)-1-(naphthen-1-yl)ethylamine by high-performance liquid chromatography using a silica-packed radial compression cartridge. The order of elution of the diastereoisomeric amides was always R, S or -, S before S,S or +,S. The conditions for the derivatization, using 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide as coupling agent, were optimized, and it was found that the addition of 1-hydroxybenzotriazole rendered the reaction quantitative. Good calibration curves were obtained for the quantitation and determination of the enantiomeric composition of 2-phenylpropionic acid in urine, and the application of the method to the study of the metabolism of this acid in vivo is described.     

Enantiomeric resolution of 2-arylpropionic acid nonsteroidal anti-inflammatory drugs by capillary electrophoresis: methods and applications

The 2-arylpropionic acids (2-APAs) are an important group of nonsteroidal anti-inflammatory drugs. These agents, the majority of which are available as racemates, exhibit stereoselectivity in both their action and disposition. Developments in stereoselective separation science methodology, mainly chromatographic, have facilitated an evaluation of the pharmacological properties of the individual enantiomers of these drugs and contributed to our understanding of both their mode(s) of action and disposition. While a number of electrophoretic techniques, including capillary electrophoresis, capillary electrochromatography and isotachophoresis, have been applied to the stereoselective resolution and stereospecific analysis of these agents using a variety of chiral selectors, e.g., cyclodextrins, oligosaccharides, macrocyclic antibiotics, and proteins, the number of published applications in pharmaceutical and biomedical analysis remains relatively limited. However, the utility of electrophoretic techniques for stereospecific analysis may be illustrated using the 2-APAs as typical examples of chiral acidic pharmaceuticals. Applications include: determination of enantiomeric composition following biosynthetic stereoselective hydrolysis; examination of both achiral and chiral impurity profiles in bulk drugs and formulated products; determination of enantiomeric impurities in both bulk drugs and formulated products; examination of configurational stability following stress testing of formulated products; determination of enantiomeric composition and metabolite profile in biological fluids following administration of the racemates and individual enantiomers. It may be anticipated that future exploitation of electrophoretic approaches to the stereospecific analysis of these agents will result in further contributions to our understanding of their stereoselective biological properties and therapeutic use.